A crosstalk between phosphorylation and ubiquitination of BNIP3 regulates mitophagy under hypoxia.

Abstract

BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3) is a mitochondrial outer membrane protein that is sensitive to hypoxia and mediates mitophagy, a process important for mitochondrial quality control and to maintain energetic and redox homeostasis under hypoxia. It has been reported that up-regulation of BNIP3, which acts as mitophagy receptor, promotes mitophagy. In our recent study, we found that the post-translational modification of BNIP3 is crucial to induce mitophagy, and that a crosstalk between phosphorylation/dephosphorylation and ubiquitination acts as a switch to control BNIP3-mediated mitophagy under hypoxia. We demonstrated that the phosphorylation of BNIP3 at S60 and T66 by MAPK8/9 (mitogen-activated protein kinase 8/9) under hypoxia blocks the degradation of BNIP3 via the ubiquitin-proteasome pathway and enhances its interaction with MAP1LC3 (microtubule associated protein 1 light chain 3), thereby promoting mitophagy. In contrast, dephosphorylation of BNIP3 by members of the PP1/2A (protein phosphatase PP1 and PP2A) phosphatase subfamily under hypoxia accelerates degradation of BNIP3 via the ubiquitin-proteasome pathway, thereby suppressing mitophagy. Altogether, these findings provide knowledge necessary to devise intervention strategies for hypoxia-related diseases and/or hypoxia-related developmental processes. Abbreviations: BCL2: BCL2 apoptosis regulator; BCL2L1: BCL2 like 1; BECN1: beclin 1, autophagy related; BH3: BCL2 homology 3; BNIP3: BCL2/adenovirus e1B 19 kDa protein interacting protein 3; LIR: MAP1LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; MAPK8: mitogen-activated protein kinase 8; MAPK9: mitogen-activated protein kinase 9; PEST: rich in amino acids P, E, S, T, and D; PP1: protein phosphatase 1; PP2A: protein phosphatase 2A; PEST: rich in amino acids P, E, S, T, and D.